2,3-Dihydro-imidazo[2,1-b]benzothiazoles

ABSTRACT

This invention relates to a novel series of 2,3-dihydroimidazo[2,1-b]benzothiazoles which display monoamine oxidase inhibiting activities.

This is a division of application Ser. No. 50,734, filed June 21, 1979,now U.S. Pat. No. 4,262,004.

BACKGROUND OF THE INVENTION

In Russian Pat. No. 443,039, in Chem. Pharm. Bull. 18 (10) 1981-1986(1970) and in Chem. Ind. 1970, (39), 1261-2 there are described a numberof imidazo[2,1-b]benzothiazole derivatives, which are useful aspharmaceuticals. The compounds of the present invention differ fromthese prior art compounds by the saturation of the double bond betweenC₂ and C₃ and by their monoamine oxidase inhibitor activities, resultingin their usefulness as antidepressants and as anti-Parkinsonism agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with novel2,3-dihydroimidazo[2,1-b]benzothiazoles, which may structurally berepresented by the formula ##STR1## and the pharmaceutically acceptableacid addition salts thereof, the imidazo[2,1-b]benzothiazolium salts offormula ##STR2## and metal salt complexes thereof, wherein: R¹ and R³are each independently selected from the group consisting of hydrogenand lower alkyl;

R² and R⁴ are each independently selected from the group consisting ofhydrogen, lower alkyl, aryl, aryllower alkyl, lower alkyloxy-lower alkylor aryloxy-lower alkyl.

R⁵, R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen; halo; nitro; alkyl having from 1 to 20 carbonatoms; cycloalkyl having from 3 to 6 carbon atoms; hydroxy; loweralkyloxy; aryloxy; α-hydroxy-arylmethyl; amino; mono- and dialkyl-amino;mono-, di- and trihalo-lower alkylamino; lower alkenylamino; loweralkynylamino; (aryl-lower alkyl)amino; (lower alkyloxy-loweralkyl)amino; (hydroxylower alkyl)amino; (aryloxy-lower alkyl)amino;[mono- and di(lower alkyl)aminolower alkyl]amino; lower alkanoylamino;N-(lower alkyl)lower alkanoylamino; aminocarbonylamino; (1-loweralkyl-4-piperidinyl)amino; cycloalkylamino wherein said cycloalkylrepresents a mono-, bi-, tri- or tetracyclic hydrocarbon radical havingfrom 3 to 10 carbon atoms; and a radical of the formula ##STR3## whereinR¹⁰ is selected from the group consisting of hydrogen, lower alkyl,lower alkenyl and lower alkynyl; or, when taken together R⁵ and R⁶, R⁶and R⁷, or R⁷ and R⁸ may form a tri- or tetramethylene bridge orcomplete a fused benzene nucleus;

R⁹ is a member selected from the group consisting of lower alkyl, loweralkenyl, lower alkynyl and aryllower alkyl; and

X is a pharmaceutically acceptable anion and n represents the valency ofthe anion;

wherein aryl as used in the foregoing definitions is phenyl, optionallysubstituted with 1 to 3 substituents each independently selected fromthe group consisting of halo, lower alkyl, lower alkyloxy andtrifluoromethyl; and aroyl is arylcarbonyl.

As used in the foregoing and in the following definitions, the term"halo" is generic to fluoro, chloro, bromo and iodo; "lower alkyl" ismeant to include straight and branched hydrocarbon radicals having from1 to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, butyl,pentyl, hexyl and the like; "alkyl" is meant to include the abovementioned meaning of "lower alkyl" and the higher homologous having from7 to 20 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl,undecyl, dodecyl and the like; "lower alkenyl" and "lower alkynyl" aremeant to include straight and branched alkenyl, respectively alkynyl,radicals having from 2 to 6 carbon atoms, such as, for example, ethenyl,2-propenyl, 2-butenyl and the like, and, respectively, ethynyl,2-propynyl, 2-butynyl and the like; "cycloalkyl, having from 3 to 6carbon atoms", as used in the definition of R⁵, R⁶, R⁷ and R⁸ refers tocyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and "cycloalkyl,having from 3 to 10 carbon atoms" as it is employed as part ofcycloalkylamino in the definition of said R⁵, R⁶, R⁷ and R⁸, refers tomono-, bi-, tri- and tetracyclic hydrocarbon radicals such as, forexample, cyclopentyl, cyclooctyl, bicyclo[3,2,1]octane,tricyclo[3,3,1,1³,7 ]decane and the like.

The anion X^(n-) in the foregoing formula (I-b) may be anypharmaceutically acceptable anion but is preferably an ion arizing froma reactive ester such as, for example, a halide ion, preferably achloride-, bromide- or iodide ion, or another ion arizing from areactive ester such as a methanesulfonate or a 4-methylphenylsulfonateion. Other pharmaceutically acceptable anions falling within the scopeof X^(n-) are, for example, anions arizing from mineral acids, e.g.,nitrate, sulfate and phosphate anions, and anions arizing frompharmaceutically acceptable organic acids such as, for example, theanions of acetic-, propanoic- and the like acids.

The compounds of formula (I-a) can be derived from an appropriatelysubstituted 2-(2-benzothiazolylamino)ethanol of formula (II) or from anappropriate 2-imino-3(2H)-benzothiazoleethanol of formula (III) bycyclizing said intermediates following art-known cyclizing procedures.##STR4## R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as previously described.

The above-mentioned cyclization-reactions may be carried out by stirringand heating the intermediates of formula (II) or (III) in an aqueousstrong acidic medium such as, for example, aqueous hydrochloric acid,aqueous sulfuric acid and the like, if desired in admixture with areaction-inert organic solvent such as 1,4-dioxane, tetrahydrofuran andthe like.

In order to improve the yields of said cyclization-reactions thehydroxyl function of the intermediates (II) or (III) may be previouslyconverted into a reactive ester residue such as, for example, halo,preferably chloro, bromo or iodo, or a sulfonyloxy group, e.g.,methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like, by reactingsaid alcohols (II) or (III) with an appropriate halogenating agent,e.g., thionyl chloride, phosphorpentabromide and the like, or with anappropriate sulfonating agent, e.g., methylsulfonyl chloride,4-methylphenylsulfonyl chloride and the like. The thus obtainedintermediates are then cyclized by stirring the latter in an appropriatesolvent such as, for example, an amide, e.g., N,N-dimethylformamide andthe like; dimethylsulfoxide and the like. Somewhat elevated temperaturesand the addition of a suitable base such as, for example, an alkalimetal or an earth alkaline metal carbonate or hydrogen carbonate, e.g.,sodium hydrogen carbonate, potassium carbonate and the like, mayadvantageously be used to enhance the rate of the reaction.

The compounds of formula (I-a) may also be prepared by cyclizing anappropriately substituted 1-aryl-4,5-dihydro-2-mercapto-1H-imidazole offormula (IV), wherein L represents an appropriate leaving group such as,for example, halo, preferably chloro, bromo or iodo. ##STR5## R¹, R²,R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as previously described.

Said cyclization-reaction may be carried out following art-knowncyclizing procedures generally known in the art, e.g., by stirring andheating the intermediate (IV) in the presence of a suitablereaction-inert solvent, e.g., N,N-dimethylformamide and the like, ifdesired in the presence of an appropriate base, e.g., sodium carbonateand the like.

Certain compounds of formula (I-a) may be derived from otherappropriately substituted compounds (I-a) by introducing or modifyingcertain substituent groups according to generally known methods ofeffecting transformations of functional groups.

Specific examples of functional group transformations which can easilybe carried out are as follows:

(i) Nitro-substituted compounds may be prepared by nitrating thecorresponding unsubstituted analogs in the usual manner, e.g., bystirring and heating a nitrate salt of the latter in an appropriatestrong acidic medium, e.g., aqueous sulfuric acid and the like.

(ii) Nitro-substituted compounds can be converted into the correspondingprimary amines according to standard nitro-to-amine reducing procedures,e.g., by catalytically hydrogenating the nitro compound in the presenceof an appropriate catalyst, e.g., Raney-nickel, palladium-on-charcoal orplatinum-on-charcoal.

(iii) Primary amines can in turn be alkylated to produce secondary andtertiary amines following standard N-alkylation procedures. For example,said N-alkylation may be performed by the reaction of the amine with anappropriate reactive ester, e.g. a halide, a methanesulfonate or a4-methylphenylsulfonate. Otherwise there may be carried out a reductiveamination by subjecting a mixture of the amine with an appropriatecarbonyl compound in the presence of an appropriate catalyst, e.g.platinum-on-charcoal to a catalytic hydrogenation.

Similarly such a reductive amination may also be achieved by reducing amixture of the amine and an appropriate carboxylic acid with anappropriate reducing agent, e.g., sodium borohydride. In order toprepare secondary amines it may be appropriate to first introduce anappropriate protecting group, thereafter introducing the desiredsubstituent, and finally removing the protecting group. An example of anappropriate protecting group is a di-(lower alkyl) 2-methylenepropanedioate radical which may easily be introduced by the reaction of theamine with a di(lower alkyl) 2-(lower alkyloxymethylene)propanedioate,and which may easily be removed by acid hydrolysis, e.g. in aqueoushydrochloric acid.

(iv) Alkanoylamino-substituted compounds can be prepared by acylatingthe corresponding amine in the usual manner with an appropriateacylating agent, e.g. an acyl halide or acid anhydride. In order toprepare formylamino-substituted compounds their may be used formaldehydeand also N,N-dimethylformamide as an acylating agent.

(v) Compounds bearing an aminocarbonylamino substituent can be preparedby reacting the corresponding amine with an appropriate alkali or earthalkaline metal cyanate, e.g. potassium cyanate and the like.

(vi) Hydroxy-substituted compounds may be derived from the correspondinglower alkyloxy- or aryllower alkyloxy-substituted compounds by treatingthe latter with a strong non-oxidizing acid, e.g. hydrobromic acid inacetic acid.

(vii) Compounds bearing an α-hydroxy-arylmethyl substituent can bederived from the corresponding aroyl-substituted analogs by reducing thecarbonyl group of the latter using an appropriate reducing agent, suchas, sodium borohydride and the like.

The compounds of formula (I-a) may conveniently be converted into theirquaternary ammonium salts of formula (I-b) by reacting a compound offormula (I-a) with a reagent of formula (V), wherein R⁹ is as previouslydefined and Z is a reactive ester group such as, for example, halo,e.g., chloro, bromo or iodo, or a sulfonyloxy group, e.g.,methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like, and, ifdesired, subsequently exchanging the anion Z of the thus obtainedcompound of formula (I-c) for another therapeutically acceptable anionX, having n as valency. ##STR6##

The reaction of (I-a) with (V) is conveniently carried out by stirringand heating the reactants together in the presence of a suitablereaction-inert solvent such as, for example, a nitrile, e.g.,acetonitrile, benzonitrile and the like; halogenated hydrocarbons, e.g.,dichloromethane; and other common solvents including dimethylformamideand the like. Most preferably, the reaction is carried out at the refluxtemperature of the reaction mixture.

The anion-exchange reaction may be accomplished following art-knownmethods such as, for example, by treating a compound of formula (I-c)with a large molar excess of an acid corresponding to the anion of thedesired salt, or, more preferably, by bringing the salt of formula (I-c)into contact with an ion-exchange resin, which is saturated with thedesired anion, and subsequently eluting the desired salt (I-b) from theresin with a suitable relatively polar solvent, or by first convertingthe salt (I-c) into the corresponding hydroxide and subsequentlyreacting the latter with an acid corresponding to the anion of thedesired salt. The salt (I-c) can be converted into the correspondinghydroxide, e.g., by its reaction with a base or by contacting said saltwith an ion-exchange resin, which is saturated with hydroxide ions, andeluting the thus obtained hydroxide from the ion-exchange resin with asuitable relatively polar solvent.

Metal salt complexes of compounds of formula (I-a) may be obtained bythe complexation of the latter with an organic or inorganic transitionmetal salt, such as, for example, halides, nitrates, sulfates,phosphates, (Z)-butenedioates and the like of copper, manganese, zinc,iron and the like transition metals, wherein said transition metals mayhave any of their naturally existing valencies.

In practice, stoechiometrically defined metal salt complexes may beprepared by dissolving a compound of formula (I-a) in a water-misciblesolvent such as, for example, warm ethanol, methanol, 1,4-dioxane orN,N-dimethylformamide, and adding thereto an aqueous solution of thedesired metal salts such as, for example, CuSO₄.5H₂ O, Mn(NO₃)₂.4H₂ O,FeCl₃.6H₂ O and the like.

A number of the intermediates used in the foregoing preparations areknown compounds, others may be prepared according to art-knownmethodologies of preparing similar compounds and some of them are noveland consequently their preparation will be described hereafter.

The intermediates of formula (II) may be prepared by cyclizing anappropriately substituted thiourea (VI) wherein the R-substituents areas previously defined and Y represents hydrogen or a reactive leavinggroup such as, for example, halo, e.g., chloro, bromo, iodo, followingart-known procedures. ##STR7##

In case Y is a reactive leaving group the cyclization-reaction can becarried out by stirring and heating the thiourea (VI) in a suitablereaction-inert organic solvent, e.g., N,N-dimethylformamide and thelike, preferably, in the presence of an appropriate base, such as analkali metal or an earth alkaline metal carbonate or hydrogen carbonateor an alkali metal hydride, e.g., sodium carbonate, sodium hydride andthe like. In case Y is hydrogen said cyclization may be carried out bystirring and heating the thiourea (VI) in a suitable reaction-inertsolvent, e.g., trichloromethane, glacial acetic acid and the like, inthe presence of a suitable halogenating agent, e.g., bromine and thelike. The latter procedure may yield directly the corresponding compoundof formula (I) when at least one of R³ and R⁴ is a sufficientlyelectronegative group such as, for example, an aryl group.

The intermediates of formula (VI), used as starting materials herein,can be prepared by reacting an appropriate arylisothiocyanate (VII) withan appropriately subsituted 2-aminoethanol (VIII). In the followingreaction equation all R-substituents have their previously definedmeanings. ##STR8##

Said reaction is carried out by stirring and, if desired, heating thereactants together in the presence of a suitable reaction-inert solventsuch as, for example, a lower alkanol, e.g., ethanol, 2-propanol and thelike.

The isothiocyanates (VII), used as starting materials herein can beprepared following art-known methods of preparing such or similarproducts.

The intermediate of formula (III) can be prepared by N-alkylating anappropriately substituted 2-aminobenzothiazole (IX) with an appropriatealcohol (X) following art-known N-alkylating procedures, i.e. bystirring and, if desired, heating the reactants together in the presenceof a suitable reaction-inert solvent such as, for example, a nitrile,e.g., acetonitrile and the like. In the following reaction equation theR-substituents are as previously defined and W represents a reactiveester residue such as, for example, halo, preferably, chloro, bromo oriodo, or a sulfonyloxy group, e.g., methylsulfonyloxy,4-methylphenylsulfonyloxy and the like. ##STR9##

The intermediates of formula (III) wherein R³ is aryl, (III-a), arepreferably prepared by the reaction of (IX) with an appropriate carbonylcompound of the formula (XI) yielding an intermediate of formula (XII),and subsequently reducing the latter with an appropriate reducing agent,e.g. sodium borohydride. The reaction of (IX) with (XI) may be carriedout following the procedure described hereabove for the reaction of (IX)with (X). ##STR10##

It is obvious that the compounds of formula (I) wherein R¹ is other thanR² and/or R³ is other than R⁴ have at least one asymmetric carbon atomand, consequently, said compounds may exist under different enantiomericforms. Pure enantiomeric forms of the compounds (I) may be obtained bythe application of art-known procedures such as, for example, separationof their diastereomeric salts with optically active acids and the likeprocedures. Isomers of compounds of formula (I) are naturally intendedto be embraced within the scope of this invention.

The compounds of formula (I) have basic properties and thus may beconverted to their therapeutically useful acid addition salts byreaction with an appropriate acid, for example, an inorganic acid suchas hydrochloric acid, i.e., hydrochloric, hydrobromic or hydroiodicacid; sulfuric, nitric or thiocyanic acid; a phosphoric acid; andorganic acid such as acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic,1,4-butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxy-1,4-butanedioic, 2,3-dihydroxy-1,4-butanedioic,2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,2-hydroxyethanesulfonic, 4-methylbenzenesulfonic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic, 2-phenoxybenzoic or 2-acetyloxybenzoic acid.The salts are in turn converted to the corresponding free bases in theusual manner, e.g. by reaction with alkali such as sodium or potassiumhydroxide.

The compounds within the scope of this invention display valuablemonoamine oxidase (M.A.O.) inhibiting properties. Monoamine oxidase hasbeen classified into two types A and B which can be differentiatedaccording to their substrate specificity and inhibitor sensitivity. Inrat brain, for instance, tryptamine is oxidatively deaminated by thetype A enzyme while β-phenylethylamine is preferentially catabolized bythe type B enzyme.

The potencies of compounds of formula (I) as M.A.O.-inhibitors weredetermined in an in-vitro experiment as described below.

PREPARATION OF THE MONOAMINE OXIDASE EXTRACT

Male Wistar rats, weighing 150 to 200 g. are killed by decapitation.Brain and other tissues are quickly removed and homogenized in an icecold 0.25 M sucrose solution with a homogenizer. The total homogenate iscentrifuged at low speed (7000 g-min) in a refrigerated centrifuge. Thesupernatant is stored at 0° C. and the sediment, which contains cellnuclei, unbroken cells and debris, is rehomogenized in an ice cold 0.25M sucrose solution and centrifuged again at 7000 g.min. The thusobtained supernatants are combined to yield the monoamine oxidaseextract.

DESCRIPTION OF THE IN-VITRO EXPERIMENTS

A mixture, containing 0.5 mmoles of [¹⁴ C]tryptamine (specific activity:50.34 mCi/mmole) or 0.5 mmoles of [¹⁴ C]phenylethylamine hydrochloride(specific activity: 50.98 mCi/mmole), 113 mmoles of potassium phosphate(pH 7.4), the substance to test and 100 μl of the hereabove describedmonoamine oxidase extract in a total volume of 0.5 ml, is incubated at37° C. for 20 minutes. The reaction is stopped by adding 0.2 ml of 2 NHCl and the reaction product is extracted in 6 ml of methylbenzene.

4 ml of the organic phase is counted for the radioactivity in a liquidscintillation spectrometer.

The data listed in tables 1 and 2 represent the concentrations of thetested compounds which inhibit 50% of the monoamine oxidase activity,using tryptamine, respectively β-phenylethylamine as substrate.

The compounds listed in the tables are not given for the purpose oflimiting the invention thereto but in order to exemplify the M.A.O.inhibitory activities of the compounds within the scope of formula (I).

                                      TABLE 1                                     __________________________________________________________________________     ##STR11##                                                                                         I.C..sub.50 -value using as substrate in                                      mole/liter:                                              R.sup.a                                                                           R.sup.b          [.sup.14 C] tryptamine                                                                 [.sup.14 C] phenylethylamine .                  __________________________________________________________________________                                  HCl                                             --  7-OH             2 × 10.sup.-6                                                                      --                                            --  5-Cl             1.2 × 10.sup.-7                                                                  6 × 10.sup.-7                             --  7-OCH.sub.3      2.8 × 10.sup.-7                                                                  1.4 × 10.sup.-5                           --  7-OC.sub.6 H.sub.5                                                                             4.5 × 10.sup.-7                                                                  9.5 × 10.sup.-8                           --  6,7-(CH.sub.2).sub.3                                                                           5.5 × 10.sup.-8                                                                  1.2 × 10.sup.-5                           --  5,6-(CHCHCHCH)   6 × 10.sup.-9                                                                    4 × 10.sup.-6                             --  7-c . C.sub.6 H.sub.11                                                                         1.2 × 10.sup.-8                                                                  6.5 × 10.sup.-8                           --  6-COC.sub.6 H.sub.5                                                                            2.2 × 10.sup.-7                                                                  3 × 10.sup.-6                             2-C.sub.6 H.sub.5                                                                 7-C.sub.3 H.sub.7                                                                              2.5 × 10.sup.-6                                                                  6 × 10.sup.-6                             --  5-CH.sub.3       2.2 × 10.sup.-7                                                                  4 × 10.sup.-6                             --  6-C.sub.2 H.sub.5                                                                              1.4 × 10.sup.-7                                                                  10.sup.-5                                       --  7-C.sub.6 H.sub.13                                                                             2 × 10.sup.-8                                                                    4 × 10.sup.-8                             --  6-NHC.sub.2 H.sub.5                                                                            1.8 × 10.sup.-8                                                                  4 × 10.sup.-5                             --  7-NHC.sub.2 H.sub.5                                                                            10.sup.-7                                                                              4.5 × 10.sup.-5                           --  8-NHC.sub.2 H.sub.5                                                                            2 × 10.sup.-9                                                                    4 × 10.sup.-5                             --  6-NHi . C.sub.3 H.sub.7                                                                        1.8 × 10.sup.-8                                                                  3.4 × 10.sup.-5                           --  7-NHCH.sub.2CCH  8 × 10.sup.-7                                                                    5.5 × 10.sup.-5                           --                                                                                 ##STR12##       1.3 × 10.sup.-7                                                                    --                                            --  6-NHCH(C.sub.2 H.sub.5).sub.2                                                                  6 × 10.sup.-9                                                                    1.8 × 10.sup.-6                           --  6-NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                              2.6 × 10.sup.-8                                                                  7 × 10.sup.-8                             --  7-NHCH.sub.2 [3,4,5-(OCH.sub.3).sub.3C.sub.6 H.sub.2 ]                                         2 × 10.sup.-5                                                                    7 × 10.sup.-8                             --  6-NHCOCH.sub.3   1.8 × 10.sup.-6                                                                  8.5 × 10.sup.-5                           --  6-NHCONH.sub.2   1.6 × 10.sup.-6                                                                  1.2 × 10.sup.-5                           --  7-NHCHC(COOEt).sub.2                                                                           3.4 × 10.sup.-6                                                                  3 × 10.sup.-8                             --  7-N(C.sub.3 H.sub.7)CHC(COOEt).sub.2                                                           2.2 × 10.sup.-7                                                                  2.2 × 10.sup.-6                           __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________                                I.C..sub.50 -value using as substrate                                         [.sup.14 C] tryptamine                                                                 [.sup.14 C] phenylethylamine             Compound                    in mole/liter                                                                          hydrochloride in mole                    __________________________________________________________________________                                         liter                                     ##STR13##                  1 × 10.sup.-9                                                                      4 × 10.sup.-5                     ##STR14##                  --       1.8 × 10.sup.-6                    __________________________________________________________________________

As can be seen from the data listed in tables 1 and 2, certain compoundswithin the scope of the present invention inhibit the enzyme activity atvery low concentration when tryptamine is used as substrate, while amuch higher concentration is required to elicit an inhibiting effectwhen a phenylethylamine substrate is used. Such compounds are preferablymonoamine oxidase inhibitors of the type A. On the other hand certaincompounds have better inhibiting properties when β-phenylethylamine isused as substrate and, obviously, such compounds have more monoamineoxidase properties of the type B.

As is generally known, compounds which are M.A.O.-inhibitors of the typeA can be used as antidepressants while M.A.O.-inhibitors of the B-typecan be used as anti-Parkinson agents. Since both types of activity arepresent in the subject compounds they can theoretically be used in bothapplications. However, it is obvious that compounds with prevailingM.A.O.-type A inhibiting activity are especially suited asantidepressants while those with prevailing M.A.O.-type B inhibitingproperties are particularly useful as anti-Parkinson agents.

In view of the useful antidepressant and anti-Parkinson activity of thesubject compounds of formula (I) this invention provides valuablepharmaceutical compositions comprising a compound of formula (I) or apharmaceutically acceptable acid addition salt or a metal salt complexthereof in an amount which is effective to treat depression and/orParkinsonism, as the active ingredient, in a solvent or a solid,semi-solid or liquid diluent or carrier. Further it provides aneffective method of treating depression, respectively Parkinsonism byadministering to the patient an amount of a compound of formula (I)which is effective in the relevant circumstances. Obviously, thecompounds of formula (I) may optionally be used in combination withother therapeutically active substances. Pharmaceutical compositionscomprising a compound of formula (I) as the active ingredient may bereadily prepared according to conventional pharmaceutical techniques forthe usual routes of administration.

Preferred compositions are in unit dosage form, comprising per dosageunit an effective quantity of the active ingredient in admixture withsuitable carriers. Although the amount of the active ingredient per unitdosage may vary within rather wide limits, dosage units comprising fromabout 1 mg to about 500 mg and more particularly from about 5 mg toabout 200 mg of the active ingredient are preferred.

The following examples are intended to illustrate and not to limit thescope of the present invention.

PREPARATION OF INTERMEDIATES EXAMPLE I

To a stirred solution of 7.5 parts of 2-aminobenzothiazole in 80 partsof acetonitrile are added 11.75 parts of2-bromo-1-(4-chlorophenyl)ethanone and the whole is stirred for about 20hours at room temperature. The precipitated product is filtered off,washed with acetonitrile, and dried, yielding 11.4 parts of1-(4-chlorophenyl)-2-(2-imino-3(2H)-benzothiazolyl)ethanonehydrobromide; mp. 261°-272° C.

To a stirred suspension of 12.5 parts of1-(4-chlorophenyl)-2-(2-imino-3(2H)-benzothiazolyl)ethanone hydrobromidein 160 parts of methanol and 100 parts of water are added portionwise1.25 parts of sodium borohydride while cooling in an ice-bath. Uponcompletion, stirring is continued for 1 h. 30 at room temperature. Thereaction mixture is evaporated in vacuo and the residue is distilled.The formed precipitate is sucked off, washed with water and dissolved intrichloromethane. The water is separated and the solution is dried andevaporated. The residue is crystallized from a mixture of methylbenzeneand petroleumether, yielding 8.9 parts ofα-(4-chlorophenyl)-2-imino-3(2H)-benzothiazoleethanone; mp. 114° C.

Example II

To a stirred and cooled (0°-5° C.) mixture of 110 parts of concentratednitric acid solution and 314 parts of concentrated sulfuric acidsolution are added dropwise 60 parts of 1,2-dichloro-4-nonylbenzene.Upon completion, stirring is continued for 30 minutes at 0° C. Thereaction mixture is poured onto crushed ice and the product is extractedwith 2,2'-oxybispropane. The extract is washed successively with waterand a sodium hydrogen carbonate solution, dried, filtered andevaporated, yielding 70 parts (100%) of1,2-dichloro-4-nitro-5-nonylbenzene as an oily residue.

Example III

To a stirred and refluxing mixture of 11.2 parts of iron, 100 parts ofammonium chloride solution 0.8 N and 20 parts of methylbenzene are added10.5 parts of (4-chloro-3-nitrophenyl)phenylmethanone and the whole isfurther stirred at reflux temperature for one hour. Methylbenzene (80parts) is added and the whole is filtered over Hyflo. The organic layeris separated, dried, filtered and evaporated. The residue is washed withcyclohexane, yielding 8.4 parts of(3-amino-4-chlorophenyl)phenylmethanone; mp. 91.9° C.

Example IV

A mixture of 120 parts of 1,2-dichloro-4-nitro-5-nonylbenzene, 2 partsof zinc chloride solution, 83 parts of sodium acetate and 480 parts ofmethanol is hydrogenated at normal pressure and at room temperature with5 parts of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The residue is dissolved in water and thesolution is alkalized with ammonium hydroxide. The product is extractedwith 2,2'-oxybispropane. The extract is washed with water, dried,filtered and evaporated. The residue is distilled, yielding 59 parts of2-nonylbenzenamine; bp. 131°-132° C. at 0.2 mm pressure.

Example V

A mixture of 34 parts of 1-(4-methyl-3-nitrophenyl)-1-butanone, 24 partsof 2-propanol saturated with hydrochloric acid and 400 parts of methanolis hydrogenated at normal pressure and at room temperature with 5 partsof palladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen is taken up, the catalyst is filtered off and the filtrate isevaporated. Water is added to the residue and the whole is alkalizedwith ammonium hydroxide. The product is extracted with2,2'-oxybispropane. The extract is dried, filtered and evaporated,yielding 25.5 parts of 5-butyl-2-methylbenzenamine as a residue.

Example VI

A mixture of 100 parts of2-chloro-5-(1,1-dimethylethyl)-1,3-dinitrobenzene and 800 parts ofmethanol is hydrogenated at normal pressure and at room temperature with10 parts of ruthenium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The residue is purified by column-chromatographyover silica gel using trichloromethane as eluent. The pure fractions arecollected and the eluent is evaporated, yielding 69 parts (78%) of2-chloro-5-(1,1-dimethylethyl)-3-nitrobenzenamine as a residue.

Example VII

A mixture of 50 parts of 2-chloro-5-nitrobenzenamine, 33.4 parts ofmethanethial and 450 parts of 1,4-dioxane is stirred and refluxed for 4hours. The reaction mixture is evaporated, yielding 62.2 parts of1-chloro-2-isothiocyanato-4-nitrobenzene as a residue.

Example VIII

A mixture of 17 parts of (3-amino-4-chlorophenyl) phenylmethanone, 9.5parts of carbonothioic dichloride and 200 parts of 1,4-dioxane isstirred and refluxed for 15 minutes. The reaction mixture is evaporatedand the oily residue is crystallized from 2,2'-oxybispropane. Theproduct is filtered off and dried, yielding 17 parts (85%) of(4-chloro-3-isothiocyanatophenyl)phenylmethanone; mp. 96.7° C.

In a similar manner there are also prepared:

1-isothiocyanato-2-nonylbenzene as a residue;

4-butyl-2-isothiocyanato-1-methylbenzene as a residue;

2-chloro-1-isothiocyanato-3-nitrobenzene as a residue;

2-chloro-5-(1,1-dimethylethyl)-1-isothiocyanato-3-nitrobenzene; mp.46.4° C.;

1-cyclohexyl-4-isothiocyanatobenzene as an oily residue; and

1-(4-isothiocyanatophenyl)nonane as a residue.

Example IX

To a stirred suspension of 29 parts of1-chloro-4-isothiocyanato-2-nitrobenzene in 120 parts of ethanol 95% areadded dropwise 8.2 parts of 2-aminoethanol (exothermic reaction: temp.rises from 25° to 32° C.). Upon completion, stirring is continued for 30minutes at room temperature. The precipitated product is filtered off(after cooling to 10° C.) and dried, yielding 30.7 parts (82.5%) ofN-(2-chloro-5-nitrophenyl)-N'-(2-hydroxyethyl)thiourea; mp. 158.4° C.

Example X

Following the procedure described in Example IX and using equivalentamounts of the appropriate starting materials there are also prepared:

    __________________________________________________________________________     ##STR15##                                                                                                     Melting point in                             R.sup.a               R.sup.b    °C.                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 OH  2-Cl,5-COC.sub.6 H.sub.5                                                                 156.7                                        CH.sub.2 CH.sub.2 OH  4-C.sub.4 H.sub.9                                                                        93.9                                         CH.sub.2 CH.sub.2 OH  2-NO.sub.2 133.0                                        CH.sub.2 CH.sub.2 OH  4-OC.sub.6 H.sub.5                                                                       118.8                                        C(CH.sub.3).sub.2 CH.sub.2 OH                                                                       2-Cl,5-NO.sub.2                                                                          170.0                                        CH.sub.2 CH.sub.2 OH  2,3-(CH.sub.2).sub.4                                                                     157.6                                        CH.sub.2 CH.sub.2 OH  2-C.sub.3 H.sub.7                                                                        110.9                                        CH.sub.2 CH.sub.2 OH  4-CH(CH.sub.3).sub.2                                                                     145.3                                        CH.sub.2 CH.sub.2 OH  3,4-(CH.sub.3).sub.2                                                                     150.2                                        CH.sub.2 CH.sub.2 OH  3,4-(CH.sub.3).sub.2                                                                     151.6                                        CH.sub.2 CH.sub.2 OH  4-C.sub.2 H.sub.5                                                                        135.3                                        CH.sub.2 CH.sub.2 OH  3-C.sub.4 H.sub.9                                                                        ±70                                       CH.sub.2 CH.sub.2 OH  3-C.sub.3 H.sub.7                                                                        ±80                                       CH.sub.2 CH.sub.2 OH  2-CH.sub.3,5-CH(CH.sub.3).sub.2                                                          --                                           CH.sub.2 CH.sub.2 OH  4-C(CH.sub.3).sub.3                                                                      158.3                                        CH.sub.2 CH.sub. 2 OH 3-C.sub.2 H.sub.5                                                                        100.1                                        CH.sub.2 CH.sub.2 OH  2-C.sub.4 H.sub.9                                                                        69.0                                         CH.sub.2 CH.sub.2 OH  3-C(CH.sub.3).sub.3                                                                      --                                           CH.sub.2 CH.sub.2 OH  2-C.sub.9 H.sub.19                                                                       --                                           CH.sub.2 CH.sub.2 OH  3,4-(CH.sub.2).sub.4                                                                     136.2                                        CH.sub.2 CH.sub.2 OH  2,5-(CH.sub.3).sub.2                                                                     158.3                                        CH.sub.2 CH.sub.2 OH  3-C.sub.5 H.sub.11                                                                       80.0                                         CH.sub.2 CH.sub.2 OH  4-C.sub.3 H.sub.7                                                                        --                                           CH.sub.2 CH.sub.2 OH  2-CH.sub.3,5-C(CH.sub.3).sub.3                                                           92.0                                         CH.sub.2 CH.sub.2 OH  2-CH.sub.3,5-F                                                                           104.0                                        CH.sub.2 CH.sub.2 OH  4-C.sub.6 H.sub.13                                                                       --                                           CH.sub.2 CH.sub.2 OH  3-C.sub.6 H.sub.13                                                                       --                                           CH.sub.2 CH.sub.2 OH  4-OC.sub.2 H.sub.5                                                                       157.6                                        CH.sub.2 CH.sub.2 OH  2-Cl,5-NO.sub.2                                                                          --                                           CH.sub.2 CH.sub.2 OH  2-Cl,3-NO.sub.2                                                                          ±170                                      CH.sub.2 CH.sub.2 OH  2,4,5-(CH.sub.3).sub.3                                                                   167.7                                        CH.sub.2 CH.sub.2 OH  2-CH.sub.3,5-C.sub.4 H.sub.9                                                             --                                           CH.sub.2 CH.sub.2 OH  2-Cl,3-NO.sub.2,5-C(CH.sub.3).sub.3                                                      --                                           CH.sub.2 CH(CH.sub.3)OH                                                                             2-Cl,5-NO.sub.2                                                                          139.0                                        CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                       --        160.8                                        CH.sub.2 CH.sub.2 OH  4-c . C.sub.6 H.sub.11                                                                   176.5                                        CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                      4-C.sub.3 H.sub.7                                                                        156.6                                        CH.sub.2 CH.sub.2 OH  4-C.sub.9 H.sub.19                                                                       98.4                                         CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                      4-C.sub.6 H.sub.13                                                                       147.7                                         ##STR16##             --        115.8                                         ##STR17##            4-C(CH.sub.3).sub.3                                                                      140.3                                         ##STR18##             --        148.9                                         ##STR19##            4-Cl       138.8                                         ##STR20##            4-C(CH.sub.3).sub.3                                                                      120.1                                         ##STR21##             --        120.0                                         ##STR22##            4-Cl       144.0                                        CH.sub.2CH(C.sub.6 H.sub.5)OH                                                                        --        129.1                                        __________________________________________________________________________

Example XI

To a stirred mixture of 6.4 parts ofN-(4-fluorophenyl)-N'-(2-hydroxyethyl)thiourea and 80 parts oftetrachloromethane is added dropwise a solution of 4.8 parts of brominein 40 parts of tetrachloromethane between 20° and 25° C. Uponcompletion, stirring is continued for 1 hour at reflux temperature. Thereaction mixture is cooled to room temperature. The precipitated productis filtered off, washed with acetonitrile and dried, yielding 5.8 partsof 2-[(6-fluoro-2-benzothiazolyl)amino]ethanol monohydrobromide; mp.163.6° C.

Example XII

Following the procedure described in Example XI and starting from thecorresponding thiourea there are also prepared:

    __________________________________________________________________________     ##STR23##                                                                                                 Salt                                                                              Melting                                                                   or  point in                                     R.sup.a           R.sup.b    Base                                                                              °C.                                   __________________________________________________________________________    CH.sub.2 CH.sub.2 OH                                                                            6-Cl       --  138.1                                        CH.sub.2 CH.sub.2 OH                                                                            4-Cl       --  102.2                                        CH.sub.2 CH.sub.2 OH                                                                            6-C.sub.4 H.sub.9                                                                        --  90.9                                         CH.sub.2 CH.sub.2 OH                                                                            4-NO.sub.2 --  143.0                                        CH.sub.2 CH.sub.2 OH                                                                            6-CH.sub.3 --  131.6                                        CH.sub.2 CH.sub.2 OH                                                                            6-OCH.sub.3                                                                              --  131.0                                        C(CH.sub.3).sub.2 CH.sub.2 OH                                                                   5-NO.sub.2 --  199.0                                        CH.sub.2 CH.sub.2 OH                                                                            4,5-(CH.sub.2).sub.4                                                                     --  118.2                                        CH.sub.2 CH.sub.2 OH                                                                            4-C.sub.3 H.sub.7                                                                        --  120.0                                        CH.sub.2 CH.sub.2 OH                                                                            4-CH.sub.3 --  107.9                                        CH.sub.2 CH.sub.2 OH                                                                            5-CH.sub.3 --  ±100                                      CH.sub.2 CH.sub.2 OH                                                                            5,6-(CH.sub.3).sub.2                                                                     --  186.7                                        CH.sub.2 CH.sub.2 OH                                                                            6-CH(CH.sub.3).sub.2                                                                     HBr 128.8                                        CH.sub.2 CH.sub.2 OH                                                                            6-C.sub.2 H.sub.5                                                                        --  115.1                                        CH.sub.2 CH.sub.2 OH                                                                            5,6-(CH.sub.2).sub.3                                                                     --  164.2                                        CH.sub.2 CH.sub.2 OH                                                                            5-C.sub.4 H.sub.9                                                                        --  --                                           CH.sub.2 CH.sub.2 OH                                                                            5,6-(CHCH  --  166.6                                                          CHCH)                                                       CH.sub.2 CH.sub.2 OH                                                                            5-C.sub.3 H.sub.7                                                                        --  72.8                                         CH.sub.2 CH.sub.2 OH                                                                            4-CH.sub.3,7-CH(CH.sub.3).sub.2                                                          --  127.9                                        CH.sub.2 CH.sub.2 OH                                                                            4,5-(CHCH  --  --                                                             CHCH)                                                       CH.sub.2 CH.sub.2 OH                                                                            4-CH(CH.sub.3).sub.2                                                                     HBr 150.7                                        CH.sub.2 CH.sub.2 OH                                                                            5-C.sub.2 H.sub.5                                                                        HBr 177.5                                        CH.sub.2 CH.sub.2 OH                                                                            4-C.sub.4 H.sub.9                                                                        --  77.1                                         CH.sub.2 CH.sub.2 OH                                                                            5-C(CH.sub.3).sub.3                                                                      HBr 97.0                                         CH.sub.2 CH.sub.2 OH                                                                            6-OC.sub.6 H.sub.5                                                                       HCl 146.4                                        CH.sub.2 CH.sub.2 OH                                                                            4-C.sub.9 H.sub.19                                                                       HBr 128.2                                        CH.sub.2 CH.sub.2 OH                                                                            6-C(CH.sub.3).sub.3                                                                      HBr --                                           CH.sub.2 CH.sub.2 OH                                                                            4,7-(CH.sub.3).sub.2                                                                     HBr 182.3                                        CH.sub.2 CH.sub.2 OH                                                                            5-C.sub.5 H.sub.11                                                                       --  --                                           CH.sub.2 CH.sub.2 OH                                                                            5,6-(CH.sub.2).sub. 4                                                                    HBr 184.4                                        CH.sub.2 CH.sub.2 OH                                                                            6-C.sub.3 H.sub.7                                                                        --  --                                           CH.sub.2 CH.sub.2 OH                                                                            4-C.sub.2 H.sub.5                                                                        --  101.1                                        CH.sub.2 CH.sub.2 OH                                                                            4-CH.sub.3,7-C(CH.sub.3).sub.3                                                           --  --                                           CH.sub.2 CH.sub.2 OH                                                                            4-CH.sub.3,7-F                                                                           HBr 160.3                                        CH.sub.2 CH.sub.2 OH                                                                            6-C.sub.6 H.sub.13                                                                       --  --                                           CH.sub.2 CH.sub.2 OH                                                                            5-C.sub.6 H.sub.13                                                                       --  --                                           CH.sub.2 CH.sub.2 OH                                                                            6-OC.sub.2 H.sub.5                                                                       --  127.0                                        CH.sub.2 CH.sub.2 OH                                                                            4,6,7-(CH.sub.3).sub.3                                                                   --  135.6                                        CH.sub.2 CH.sub.2 OH                                                                            4-CH.sub.3,7-C.sub.4 H.sub.9                                                             --  --                                           CH.sub.2 CH.sub.2 OH                                                                            6-c . C.sub.6 H.sub.11                                                                   1/2H.sub.2 O                                                                      141.1                                        CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                  --         --  166.2                                         ##STR24##        --         --  144.6                                        CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                  6-C.sub.3 H.sub.7                                                                        --  161.9                                        CH(C.sub.6 H.sub.5)CH.sub.2 OH                                                                  6-C.sub.6 H.sub.13                                                                       --  112.7                                        CH.sub.2 CH.sub.2 OH                                                                            6-C.sub.9 H.sub.19                                                                       --  100.9                                         ##STR25##        --         --  162.5                                         ##STR26##        6-C(CH.sub.3).sub.3                                                                      --  194.4                                         ##STR27##        6-Cl       --  161.1                                         ##STR28##        6-C(CH.sub.3).sub.3                                                                      --  162.3                                         ##STR29##        6-Cl       --  134.0                                         ##STR30##        --         --  128.7                                         ##STR31##        --         --  --                                           __________________________________________________________________________

Example XIII

A mixture of 116 parts ofN-(2-chloro-5-nitrophenyl)-N'-(2-hydroxy-1-phenylethyl)thiourea, 50parts of potassium carbonate and 675 parts of N,N-dimethylacetamide isstirred and refluxed for 1 hour. The reaction mixture is poured onto2000 parts of water. After cooling, the whole is filtered over Hyflo andthe product is allowed to crystallize from the filtrate. It is filteredoff and dried, yielding 23 parts ofβ-(5-nitro-2-benzothiazolylamino)benzeneethanol.

In a similar manner there is also prepared:

2-(7-nitro-2-benzothiazolylamino)ethanol; mp. 176.8° C.

Example XIV

A mixture of 28 parts ofN-(2-chloro-5-nitrophenyl)-N'-(2-hydroxyethyl)thiourea, 14.5 parts ofpotassium carbonate and 225 parts of N,N-dimethylformamide is stirredand refluxed for one hour. After cooling, 300 parts of water are added.The precipitated product is filtered off, washed with water and dried,yielding 20.5 parts (82%) of 2-[(5-nitro-2-benzothiazolyl)amino]ethanol;mp. 183.4° C.

In a similar manner there are also prepared:

2-{[5-(1,1-dimethylethyl)-7-nitro-2-benzothiazolyl]amino}ethanol; mp.200.7° C.; and

1-[(5-nitro-2-benzothiazolyl)amino]-2-propanol; mp. 200° C.

Example XV

A mixture of 6 parts ofN-(5-benzoyl-2-chlorophenyl)-N'-(2-hydroxyethyl)thiourea, 2.5 parts ofsodium hydride dispersion 75% and 90 parts of N,N-dimethylacetamide isstirred and heated quickly to 130° C. The reaction mixture is cooled,water is added and the whole is allowed to stand overnight. Theprecipitated product is filtered off, washed with water and crystallizedfrom ethanol, yielding 2.8 parts of{2-[(2-hydroxyethyl)amino]-5-benzothiazolyl}phenylmethanone; mp. 159° C.

PREPARATION OF FINAL COMPOUNDS Example XVI

To a stirred and cooled (0° C.) solution of 19 parts of2-[(5-nitro-2-benzothiazolyl)amino]ethanol in 18 parts ofN,N-dimethylformamide is added dropwise (slowly) a solution of 10.7parts of thionyl chloride in 207 parts of N,N-dimethylformamide. Uponcompletion, the mixture is stirred and heated slowly to reflux andstirring at reflux is continued for 4 hours. After cooling, theprecipitated product is filtered off and washed withN,N-dimethylformamide and 2,2'-oxybispropane, yielding 17.5 parts (85%)of 2,3-dihydro-6-nitroimidazo[2,1-b]benzothiazole monohydrochloride; mp.314°-316° C. (dec.).

Example XVII

Following the cyclization-procedure described in Example XVI andstarting from an appropriately substituted2-[(2-benzothiazolyl)amino]ethanol there are also prepared:

    __________________________________________________________________________     ##STR32##                                                                                               Salt   Melting                                                                or     point in                                    R.sup.a      R.sup.b       Base   °C.                                  __________________________________________________________________________      --           --          HCl    231.0                                         --         6-COC.sub.6 H.sub.5                                                                         HCl    267.0                                         --         7-F            --    98.8                                          --         7-Cl           --    179.9                                         --         5-Cl           --    166.3                                         --         5-NO.sub.2    HCl    263.3                                         --         7-n . C.sub.4 H.sub.9                                                                       HCl . 1/2H.sub.2 O                                                                   135.2                                         --         7-CH.sub.3    HCl    +300° C.                               --         7-OCH.sub.3   HCl    222.7                                       2-CH.sub.3,2-CH.sub.3                                                                      6-NO.sub.2     --    217.0                                         --         5,6-(CH.sub.2).sub.4                                                                        HCl    287.6                                         --         6-CH.sub.3    HCl    +300                                           --        5-n . C.sub.3 H.sub.7                                                                       HCl    221.2                                         --         5-CH.sub.3    HCl    293.4                                         --         6-CH.sub.3,7-CH.sub.3                                                                       HCl    292.1                                         --         7-i . C.sub.3 H.sub.7                                                                       (COOH).sub.2                                                                         183.9                                         --         7-C.sub.2 H.sub.5                                                                           HCl    198.9                                         --         6-n . C.sub.4 H.sub.9                                                                       HCl . 1/2H.sub.2 O                                                                   207.8                                         --         6,7-(CH.sub.2).sub.3                                                                        HCl    295-312                                       --         6-n . C.sub.3 H.sub.7                                                                       HCl    232.4                                         --         6,7-(CHCHCHCH)                                                                              HCl    237.0                                         --         5-CH.sub.3,8-i . C.sub.3 H.sub.7                                                            HCl    229.1                                         --         5,6-(CHCHCHCH)                                                                              HCl    296.3                                         --         5-n . C.sub.4 H.sub.9                                                                       HCl    225.6                                         --         5-i . C.sub.3 H.sub.7                                                                       HCl    271.2                                         --         6-t . C.sub.4 H.sub.9                                                                       HCl    256.1                                         --         7-OC.sub.6 H.sub.5                                                                          HCl    222.4                                         --         5-n . C.sub.9 H.sub.19                                                                       --    79.2                                          --         7-t . C.sub.4 H.sub.9                                                                        --    120.3                                         --         6-C.sub.2 H.sub.5                                                                           HCl    242.2                                         --         5-CH.sub.3,8-CH.sub.3                                                                       HCl    +300                                          --         6-n . C.sub.5 H.sub.11                                                                      HCl    193.4                                         --         5-CH.sub.3,8-t . C.sub.4 H.sub.9                                                             --    145.6                                         --         6,7-(CH.sub.2).sub.4                                                                         --    116.1                                         --         7-n . C.sub.3 H.sub.7                                                                       HCl    164.6                                         --         5-CH.sub.3,8-F                                                                              HCl    282.3                                         --         5-C.sub.2 H.sub.5                                                                           HCl    239.1                                         --         7-n . C.sub.6 H.sub.13                                                                      HCl 1/2H.sub.2 O                                                                     144.6                                         --         6-n . C.sub.6 H.sub.13                                                                      HCl    154.2                                         --         7-OC.sub.2 H.sub.5                                                                           --    88.3                                        2-C.sub.6 H.sub.5                                                                          6-NO.sub.2    HCl    258.4                                         --         8-NO.sub.2     --    182.4                                         --         5-CH.sub.3,7-CH.sub.3,8-CH.sub.3                                                             --    154.8                                         --         5-CH.sub.3,8-n . C.sub.4 H.sub.9                                                             --    64.0                                          --         6-t . C.sub.4 H.sub.9,8-NO.sub.2                                                             --    200.0                                       3-CH.sub.3   6-NO.sub. 2    --     --                                           --         7-C.sub.6 H.sub.5                                                                            --    114.9                                       3-CH.sub.2 O(4-BrC.sub.6 H.sub.4)                                                            --          HCl    224.7                                       2-C.sub.6 H.sub.5                                                                          7-n . C.sub.4 H.sub.9                                                                       HCl    220.5                                       3-CH.sub.2 O(4-t . C.sub.4 H.sub.9C.sub.6 H.sub.4)                                           --           --    110.8                                       2-C.sub.6 H.sub.5                                                                            --           --    97.0                                        3-CH.sub.2 O(4-FC.sub.6 H.sub.4)                                                           7-Cl           --    139.0                                       2-C.sub.6 H.sub.5                                                                          7-n . C.sub.6 H.sub.13                                                                      HCl    179.7                                         --         7-n . C.sub.9 H.sub.19                                                                      HCl    152.9                                       2-CH.sub.2 O(4-t . C.sub.4 H.sub.9 C.sub.6 H.sub.4)                                        7-t . C.sub.4 H.sub.9                                                                       HCl    265.2                                       3-CH.sub.2 O(4-CH.sub.3 C.sub.6 H.sub.4)                                                     --          HCl    202.2                                       3-CH.sub.2 O(2-ClC.sub.6 H.sub.4)                                                          7-Cl           --    175.4                                       3-CH.sub.2 O(4-FC.sub.6 H.sub.4)                                                           7-t . C.sub.4 H.sub.9                                                                        --    137.1                                       3-CH.sub.2 O(2-ClC.sub.6 H.sub.4)                                                            --           --    132.6                                       __________________________________________________________________________

Example XVIII

A mixture of 4 parts ofα-(4-chlorophenyl)-2-imino-3-benzothiazolineethanol and 23 parts ofconcentrated sulfuric acid is stirred first for 30 minutes in anice-bath and further for 1 h. 30 at room temperature. The reactionmixture is poured onto crushed ice, alkalized with ammonium hydroxideand the product is extracted with trichloromethane. The extract isdried, filtered and evaporated. The solid residue is crystallized from2-propanol, yielding 1.6 parts of2-(4-chlorophenyl)-2,3-dihydroimidazo[2,1-b]benzothiazole; mp. 143.3° C.

Example XIX

A mixture of 50 parts of N-(2-hydroxy-2-phenylethyl)-N'-phenylthiourea,30 parts of bromine and 800 parts of tetrachloromethane is stirred andrefluxed for 2 hours. The reaction mixture is evaporated. From theresidue, the free base is liberated in the conventional manner withammonium hydroxide and extracted with trichloromethane. The extract isdried, filtered and evaporated. The residue is suspended in boiling4-methyl-2-pentanone. The product is filtered off and stirred in adiluted sodium hydroxide solution. The product is extracted with4-methyl-2-pentanone. The extract is washed with water, dried, filteredand evaporated. The residue is crystallized from acetonitrile. Theproduct is filtered off and dried, yielding 10 parts (22%) of2,3-dihydro-3-phenylimidazo[2,1-b]benzothiazole; mp. 131.7° C.

Example XX

To a stirred solution of 95 parts of2,3-dihydroimidazo-[2,1-b]benzothiazole in 480 parts of 2-propanol areadded 57 parts of nitric acid solution 66%. The formed nitrate salt isfiltered off and dried, yielding 129 parts (100%) of2,3-dihydroimidazo[2,1-b]benzothiazole mononitrate; mp. 163.7° C.

Example XXI

10 Parts of 2,3-dihydroimidazo[2,1-b]benzothiazole mononitrate are addedportionwise to 55.2 parts of concentrated sulfuric acid at 0° C. Uponcompletion, stirring is continued for 30 minutes at room temperature.The reaction mixture is poured onto crushed ice and the whole isalkalized with ammonium hydroxide at a temperature below 20° C. Theproduct is extracted with a mixture of trichloromethane and methanol(90:10 by volume). The extract is washed with water, dried, filtered andevaporated. The residue is crystallized from 160 parts of 1-butanol. Theproduct is filtered off and dried, yielding 8 parts (80%) of2,3-dihydro-7-nitroimidazol[2,1-b]benzothiazole; mp. 238.9° C.

In a similar manner there are also prepared:

    ______________________________________                                         ##STR33##                                                                                              Salt     Melting                                                              or       point in                                   R.sup.a  R.sup.b          base     °C.                                 ______________________________________                                        --       5-CH.sub.3,7-NO.sub.2,8-i . C.sub.3 H.sub.7                                                    --       139.2                                      --       6-NO.sub.2,7-n . C.sub.6 H.sub.13                                                              --       95.7                                       --       5-CH.sub.3,7-NO.sub.2,8-CH.sub.3                                                               --       207.6                                      --       6-NO.sub.2,7-C.sub.2 H.sub.5                                                                   --       176.9                                      --       6-NO.sub.2,7-n . C.sub.3 H.sub.7                                                               --       --                                         --       6-NO.sub.2,7-n . C.sub.4 H.sub.9                                                               --       123-125                                    --       5-CH.sub.3,6-NO.sub.2,7-CH.sub.3,8-CH.sub.3                                                    --       217.0                                      --       6-NO.sub.2,7-CH.sub.3                                                                          --       233.6                                      ______________________________________                                    

Example XXII

A mixture of 11 parts of 2,3-dihydro-6-nitroimidazo-[2,1-b]benzothiazoleand 80 parts of methanol is hydrogenated at normal pressure and at roomtemperature with 5 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated. The residue is crystallized fromdimethylbenzene. The product is filtered off and dried, yielding 5.6parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine; mp. 204°-210° C.

Following the same nitro-to-amine reduction there is also prepared:

2,3-dihydroimidazo[2,1-b]benzothiazol-7-amine; mp. 212°-216° C.

Example XXIII

A mixture of 5.5 parts of2,3-dihydro-5-nitroimidazo-[2,1-b]benzothiazole and 160 parts ofmethanol, saturated with ammonia is hydrogenated at normal pressure andat room temperature with 2 parts of platinum-on-charcoal catalyst 5%.After the calculated amount of hydrogen is taken up, the catalyst isfiltered off and the filtrate is evaporated. The residue is crystallizedfrom 1-butanol. The product is filtered off and dried, yielding 3 partsof 2,3-dihydroimidazo[2,1-b]benzothiazol-5-amine; mp. 229.2° C.

In a similar manner there are also prepared:

    ______________________________________                                         ##STR34##                                                                                              Salt     Melting                                                              or       point in                                   R.sup.a   R.sup.b         base     °C.                                 ______________________________________                                        2-CH.sub.3,2-CH.sub.3                                                                   6-NH.sub.2      --       198.0                                      --        5-CH.sub.3,7-NH.sub.2,8-i . C.sub.3 H.sub.7                                                   --       263.0                                      --        6-NH.sub.2,7-n . C.sub.6 H.sub.13                                                             --       136.6                                      --        5-CH.sub.3,7-NH.sub.2,8-CH.sub.3                                                              --       --                                         2-C.sub.6 H.sub.5                                                                       6-NH.sub.2      --       --                                         --        8-NH.sub.2      --       199.0                                      --        6-NH.sub.2,7-C.sub.2 H.sub.5                                                                  --       235-242                                    --        6-NH.sub.2,7-n . C.sub.3 H.sub.7                                                              --       181-185.4                                  --        6-NH.sub.2,7-n . C.sub.4 H.sub.9                                                              --       153.1                                      --        6-t . C.sub.4 H.sub.9 ,8-NH.sub.2                                                             --       170.0                                      --        6-NH.sub.2,7-CH.sub.3                                                                         --       226.3                                      3-CH.sub.3                                                                              6-NH.sub.2      2HCl .   279.2                                                                1/2H.sub.2 O                                        ______________________________________                                    

Example XXIV

A mixture of 5.5 parts of imidazo[2,1-b]benzothiazol-6-amine and 7.5parts of diethyl 2-(ethoxymethylene)propanedioate is stirred for 30minutes at 110° C. The solid product is suspended in 1,1'-oxybisethane.It is filtered off and dried, yielding 10 parts (95%) of diethyl2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)aminomethylene]propanedioate;mp 140° C.

In a similar manner the following compounds are prepared starting froman appropriate amine and diethyl-2-(ethoxymethylene)propanedioate:

diethyl2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-7-yl-amino)methylene]propanedioate;mp. 156.1° C.;

diethyl2-{[2,3-dihydro-5-methyl-8-(1-methylethyl)imidazo[2,1-b]benzothiazol-7-yl]aminomethylene}propanedioate;mp. 142.3° C.;

diethyl2-[(7-ethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)aminomethylene]propanedioatehemihydrate; mp. 133.7° C.;

diethyl2-[(7-butyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)aminomethylene]propanedioate;mp. 133.2° C.;

diethyl2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-8-yl)aminomethylene]propanedioate;mp. 142.7° C.;

diethyl2-[(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-ylamino)methylene]propanedioate;mp. 180.5° C.;

diethyl2-{[6-(1,1-dimethylethyl)-2,3-dihydroimidazo[2,1-b]benzothiazol-8-yl]aminomethylene}propanedioate;mp. 151.5° C.;

diethyl2-[(7-hexyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-ylamino)methylene]propanedioate;mp. 99.8° C.; and

diethyl2-[(2,3-dihydro-3-methylimidazo[2,1-b]benzothiazol-6-ylamino)methylene]propanedioate;mp. 110° C.

Example XXV

To a stirred solution of 10 parts of diethyl2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-6yl)aminomethylene]propanedioate in 100 parts of hexamethylphosphorictriamide are added portionwise 1.1 parts of sodium hydride dispersion76.1%: exothermic reaction (temp. rises to 36° C.). After stirring for30 minutes at room temperature, 5.55 parts of diethyl sulfate are addeddropwise. Upon completion, stirring is continued first for 8 hours at40° C. and further overnight at room temperature. 450 Parts ofmethylbenzene are added and the whole is washed three times with 200parts of water. The organic phase is dried, filtered and evaporated,yielding 12 parts of diethyl2-{[(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)ethylamino]methylene}propanedioateas an oily residue.

Following the same procedure and using equivalent amounts of theappropriate starting materials there are prepared:

    ______________________________________                                         ##STR35##                                                                                                         Melt-                                                                  Salt   ing                                                                    or     point                                    R.sup.a                                                                             R.sup.b                 base   in °C.                            ______________________________________                                        --    7-N(n . C.sub.3 H.sub.7)CHC(COOC.sub.2 H.sub.5).sub.2                                                 --     103.0                                    --    7-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2                                                            --     --                                       --    6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2                                                            --     141.7                                    --    6-N(nC.sub.3 H.sub.7)CHC(COOC.sub.2 H.sub.5).sub.2                                                    --     145.6                                    --    7-N(CH.sub.2 CCH)CHC(COOC.sub.2 H.sub.5).sub.2                                                        --     120.0                                    --    7-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2                                                     --     --                                       --    7-N(n . C.sub.4 H.sub.9)CHC(COOC.sub.2 H.sub.5).sub.2                                                 --     --                                       --    7-N(n . C.sub.6 H.sub.13)CHC(COOC.sub.2 H.sub.5).sub.2                                                --     --                                       --    7-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                   --     --                                             5-CH.sub.3 ;8-i . C.sub.3 H.sub.7                                       --    6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2 ;7-C.sub.2 H.sub.5                                         --     --                                       --    6-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                   --     --                                             7-C.sub.2 H.sub.5                                                       --    6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                          --     --                                             7-n . C.sub.4 H.sub.9                                                   --    8-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2                                                     --     --                                       --    6-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                   --     --                                             7-n . C.sub.4 H.sub.9                                                   --    6-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2 ;7-CH.sub.3                                         --     --                                       --    8-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub. 2 ;                                                  --     --                                             6-t . C.sub.4 H.sub.9                                                   --    6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                          --     --                                             7-CH.sub.3                                                              --    6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                          --     --                                             7-n . C.sub.5 H.sub.11                                                  --    6-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                                   --     --                                             7-n . C.sub.6 H.sub.13                                                  --    6-N(n . C.sub.3 H.sub.7)CHC(COOC.sub.2 H.sub.5).sub.2 ;                                               --     --                                             7-CH.sub.3                                                              3-CH.sub.3                                                                          6-N(CH.sub.3)CHC(COOC.sub.2 H.sub.5).sub.2                                                            --     --                                       3-CH.sub.3                                                                          6-N(C.sub.2 H.sub.5)CHC(COOC.sub.2 H.sub.5).sub.2                                                     --     --                                       ______________________________________                                    

Example XXVI

A mixture of 12 parts of diethyl2-{[(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)ethylamino]methylene}propanedioate,36 parts of concentrated hydrochloric acid and 30 parts of water isstirred and refluxed for 15 minutes. The reaction mixture is cooled andalkalized with ammonium hydroxide. The product is extracted withmethylbenzene. The extract is washed with water, dried, filtered andevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 2 parts ofN-ethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine; mp. 239°-246° C.

In a similar manner there are also prepared:

    ______________________________________                                         ##STR36##                                                                                             Salt or  Melting point                               R.sup.a                                                                             R.sup.b            base     in °C.                               ______________________________________                                        --    7-NHn . C.sub.3 H.sub.7                                                                          --       173.4-175.4                                 --    7-NHCH.sub.3       --       207.5                                       --    6-NHn . C.sub.3 H.sub.7                                                                          --       153.4                                       --    6-NHCH.sub.3       --       218.3                                       --    7-NHCH.sub.2 CCH   --       146.6                                       --    7-NHC.sub.2 H.sub.5                                                                              --       186.4                                       --    7-NHn . C.sub.4 H.sub.9                                                                          --       147.5                                       --    7-NHn . C.sub.6 H.sub.13                                                                         --       133.1                                       --    5-CH.sub.3,7-NHC.sub.2 H.sub.5,8-i . C.sub.3 H.sub.9                                             --       136.2                                       --    6-NHCH.sub.3,7-C.sub.2 H.sub.5                                                                   --       233.4                                       --    6-NHC.sub.2 H.sub. 5,7-C.sub.2 H.sub.5                                                           --       137.2                                       --    6-NHCH.sub.3,7-n . C.sub.4 H.sub.9                                                               --       147.1                                       --    8-NHC.sub.2 H.sub.5                                                                              --       144.0                                       --    6-NHC.sub.2 H.sub.5,7-n . C.sub.4 H.sub.9                                                        --       116.3                                       --    6-NHC.sub.2 H.sub.5,7-CH.sub.3                                                                   --       199.7                                       --    6-t . C.sub.4 H.sub.9,8-NHC.sub.2 H.sub.5                                                        --       168.4                                       --    6-NHCH.sub.3,7-CH.sub.3                                                                          --       263.7                                       --    6-NHCH.sub.3,7-n . C.sub.6 H.sub.13                                                              --       136.4                                       --    6-NHC.sub.2 H.sub.5,7-n . C.sub.6 H.sub.13                                                       --       80.7                                        --    6-NHn . C.sub.3 H.sub.7,7-CH.sub.3                                                               --       119.4                                       3-CH.sub.3                                                                          6-NHCH.sub.3       --       144.9                                       3-CH.sub.3                                                                          6-NHC.sub.2 H.sub.5                                                                              --       124.9                                       ______________________________________                                    

Example XXVII

To a stirred mixture of 4 parts of imidazo[2,1-b]benzothiazol-6-amineand 30 parts of acetic acid are added 1.6 parts of 2-propanone. Afterstirring for 10 minutes at room temperature, 0.6 parts of sodiumborohydride are added portionwise at 20° C. (cooling is necessary). Uponcompletion, stirring is continued for 10 minutes. The reaction mixtureis poured onto water and the whole is alkalized to pH 7-8 with ammoniumhydroxide. The product is extracted with trichloromethane. The extractis washed with water, dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume), saturated with ammonia,as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from 4-methyl-2-pentanone. Theproduct is filtered off and dried, yielding 2.5 parts (54%) of2,3-dihydro-N-(1-methylethyl)imidazo[2,1-b]benzothiazol-6-amine; mp.128.2° C.

    ______________________________________                                         ##STR37##                                                                                                        Melting                                                              Salt or  point                                     R.sup.a                                                                              R.sup.b             base     in °C.                             ______________________________________                                        --     6-NHc . C.sub.5 H.sub.9                                                                           --       146.8                                     --     6-NHc . C.sub.6 H.sub.11                                                                          --       159.3                                     --                                                                                    ##STR38##          --       187.0                                     --     7-NHc . C.sub.6 H.sub.11                                                                          --       164.1                                     --     7-NHc . C.sub.5 H.sub.9                                                                           --       143.7                                     --                                                                                    ##STR39##          --       179.1                                     --     7-NHi . C.sub.3 H.sub.7                                                                           --       146.9                                     --     7-NHCH.sub.2C.sub.6 H.sub.5                                                                       --       135.5                                     --     7-NHadamantyl       --       175.0                                     --     7-NHc . C.sub.7 H.sub.13                                                                          2HCl     266.5                                     --     7-NHCH(C.sub.2 H.sub.5).sub.2                                                                     --       170.2                                     --     7-NHCH.sub.2 [(3,4,5-(OCH.sub.3).sub.3                                                            2HCl     210.8                                            C.sub.6 H.sub.2 ]                                                      --     6-NHCH(C.sub.2 H.sub.5).sub.2                                                                              125.3                                     --                                                                                    ##STR40##          3HCl . H.sub.2 O                                                                       209.1                                     --     5-NHCH(CH.sub.3).sub.2                                                                            HCl      259.8                                     --     7-NHCH(CH.sub.3)C.sub.2 H.sub.5                                                                   --       137.5                                     --     7-NHCH(CH.sub.3)n . C.sub.3 H.sub.7                                                               --       112.0                                     --     6-NHCH(CH.sub.3)n . C.sub.3 H.sub.7                                                               --       108.5                                     --     6-NHCH(CH.sub.3)C.sub.2 H.sub.5                                                                   --       117.4                                     --     7-NHCH(CH.sub.3)i . C.sub.3 H.sub.7                                                               --       154.1                                     --     7-NHCH(CH.sub.3)n . C.sub.4 H.sub.9                                                               --       106.5                                     --     6-NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                                 --       178.9                                     2-CH.sub.3,                                                                          6-NHi . C.sub.3 H.sub.7                                                                           HCl      234.9                                     2-CH.sub.3                                                                    --     7-NHCH.sub.2C(CH.sub.3).sub.3                                                                     --       145.3                                     --     6-NHCH.sub.2C(CH.sub.3).sub.3                                                                     --       158.9                                     --     7-NHCH.sub.2(2,4-Cl.sub.2                                                                         2HCl .   >300                                             C.sub.6 H.sub.3)    1/2H.sub.2 O                                       --     6-NHCH.sub.2 (4-OCH.sub.3                                                                         --       165.5                                            C.sub.6 H.sub.4)                                                       --     7-NHCH.sub.2 (4-CH.sub.3C.sub.6 H.sub.4)                                                          --       164.1                                     --     6-NHCH.sub.2 [(3,4,5-                                                                             1/2      168.0                                            (OCH.sub.3).sub.3C.sub.6 H.sub.2 ]                                                                C.sub.2 H.sub.5 OH                                 --     5-NHCH.sub.2 [(3,4,5-                                                                             --       142.9                                            (OCH.sub.3).sub.3C.sub.6 H.sub.2 ]                                     --     5-CH.sub.3,7-NHi . C.sub.3 H.sub.7,                                                               --       125.8                                            8-i . C.sub.3 H.sub.7                                                  --     5-CH.sub.3,7-NHc . C.sub.5 H.sub.9,                                                               2HCl .   243.1                                            8-i . C.sub.3 H.sub.7                                                                             2H.sub.2 O                                         --     5-CH.sub.3,7-NHCH(C.sub.2 H.sub.5).sub.2                                                          2HCl .   219.8                                            8-i . C.sub.3 H.sub.7                                                                             2H.sub.2 O                                         --     5-CH.sub.3,7-NHi . C.sub.3 H.sub.7,                                                               --       134.1                                            8-CH.sub.3                                                             --     6-NHi . C.sub.3 H.sub.7,7-n . C.sub.6 H.sub.13                                                    2HCl     210.6                                                                1/2H.sub.2 O                                       2-C.sub.6 H.sub.5                                                                    6-NHi . C.sub.3 H.sub.7                                                                           --       133.2                                     --     8-NHi . C.sub.3 H.sub.7                                                                           --       133.9                                     --     6-NHCH(CH.sub.3)CH.sub.2 OH                                                                       --       227.9                                     --     6-NHc . C.sub.5 H.sub.9,7-C.sub.2 H.sub.5                                                         --       126.8                                     --     6-NHCH(C.sub.2 H.sub.5).sub.2 7-C.sub.2 H.sub.5                                                   HCl .    183.6                                                                1/2H.sub.2 O                                       --     6-NHi . C.sub.3 H.sub.7,7-C.sub.2 H.sub.5                                                         HCl      257.0                                     --     8-NHCH(C.sub.2 H.sub.5).sub.2                                                                     --       145.4                                     --     6-NHCH(CH.sub.3).sub.2,7-                                                                         --       51.5                                             n . C.sub.4 H.sub.9                                                    --     6-NHCH(C.sub.2 H.sub.5).sub.2,7-n . C.sub.4 H.sub.9                                               --       69.4                                      --     6-NHc . C.sub.5 H.sub.9,7-n . C.sub.4 H.sub.9                                                     --       86.3                                      --     6-NHCH(C.sub.2 H.sub.5).sub.2,7-CH.sub.3                                                          --       74.7                                      --     6-NHi . C.sub.3 H.sub.7,7-CH.sub.3                                                                --       159.3                                     --     6-NHc . C.sub.5 H.sub.9,7-CH.sub.3                                                                --       156.0                                     --     6-NHCH(CH.sub.3)CH.sub.2 OH,7-CH.sub.3                                                            --       204.2                                     --     6-t . C.sub.4 H.sub.9,8-NHi . C.sub.3 H.sub.7                                                     --       185.4                                     --     6-NHCH(CH.sub.3)CH.sub.2 OH,7-C.sub.2 H.sub.5                                                     --       177.5                                     --     6-NHCH(CH.sub.3)CH.sub.2 OH,                                                                      --       161.0                                            7-n . C.sub.4 H.sub.9                                                  --     6-NHc . C.sub.5 H.sub.9,7-n . C.sub.6 H.sub.13                                                    HCl      208.2                                     --     6-NHCH(C.sub.2 H.sub.5).sub.2,7-n . C.sub.6 H.sub.13                                              HCl      177.3                                     --     6-NHCH(CH.sub.3).sub.2                                                                            2HCl     239.6                                     ______________________________________                                    

Example XXVIII

To a stirred mixture of 60 parts of trifluoroacetic acid and 4 parts ofsodium borohydride are added portionwise, during a 5 hours-period, 4parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine at 30°-40° C. Thereaction mixture is poured onto 300 parts of ice-water. The precipitatedproduct is filtered off, washed with water and taken up intrichloromethane. The mixture is washed with ammonium hydroxide. Theorganic phase is dried, filtered and evaporated. The residue iscrystallized from acetonitrile, yielding 3.3 parts of2,3-dihydro-N-(2,2,2-trifluoroethyl)imidazo[2,1-b]benzothiazol-6-amine;mp. 211.7° C.

Example XXIX

To a stirred and cooled mixture of 5 parts of2,3-dihydroimidazo[2,1-b]benzothiazol-7-amine and 200 parts of formicacid are added portionwise 9.8 parts of sodium borohydride whilenitrogen gas is introduced. Upon completion, stirring is continued firstfor 1 hour at 40° C. and further overnight at room temperature. Thereaction mixture is evaporated and 500 parts of water are added to theresidue. The aqueous phase is washed with 4-methyl-2-pentanone andfiltered over hyflo. The filtrate is alkalized with ammonium hydroxideand the product is extracted with trichloromethane. The extract iswashed with water, dried, filtered and evaporated. The residue ispurified by column-chromatography over silica gel using a mixture oftrichloromethane and methanol (93:7 by volume), saturated with ammonia,as eluent. The pure fractions are collected and the eluent isevaporated. The residue is crystallized from a mixture of methylbenzeneand 2,2'-oxybispropane. The product is filtered off and dried, yielding2.4 parts of 2,3-dihydro-N,N-dimethylimidazo[2,1-b]benzothiazol-7-amine;mp. 144.3° C.

In a similar manner there are also prepared:

2,3-dihydro-N,N-dipropylimidazo[2,1-b]benzothiazol-7-amine; mp. 82° C.;

N,N-diethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine; mp. 136.2°C., and

2,3-dihydro-N,N-dimethylimidazo[2,1-b]benzothiazol-6-amine; mp. 171° C.

Example XXX

To a stirred mixture of 360 parts of formic acid and 7.5 parts of2,3-dihydroimidazo[2,1-b]benzothiazol-8-amine are added portionwise,during a 2 hours-period, 14.7 parts of sodium borohydride while nitrogengas is introduced and the temperature is kept at about 30° C. Uponcompletion, stirring is continued first for 1 hour at about 60° C. andfurther overnight at room temperature. 200 Parts of water are added tothe reaction mixture and the whole is alkalized with ammonium hydroxideat a temperature below 10° C. The produce is extracted with warmtrichloromethane. The extract is filtered over Hyflo and the filtrate isevaporated. The residue is boiled in 1,1'-oxybisethane. The product isfiltered off (the filtrate is set aside) and dried, yielding 1 part ofN-(2,3-dihydroimidazo[2,1-b]benzothiazol-8-yl)formamide; mp. 217° C.

The filtrate, which was set aside (see above), is evaporated. Theresidue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (95:5 by volume), saturatedwith ammonia, as eluent. The pure fractions are collected and the eluentis evaporated. The residue is converted into the hydrochloride salt in2-propanol. The salt is filtered off and recrystallized from2-propanone, yielding 1.1 parts of2,3-dihydro-N,N-dimethylimidazo[2,1-b]benzothiazol-8-aminedihydrochloride hemihydrate; mp. 205.9° C.

Examplle XXXI

A mixture of 7 parts of dimethyl carbonate, 3 parts of2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine and 70 parts of water isstirred and refluxed for 1 hour. The reaction mixture is cooled andalkalized with ammonium hydroxide.

The precipitated product is filtered off and crystallized from ethanol,yielding 1.6 parts ofN-(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)acetamide; mp. 268° C.

Example XXXII

A mixture of 10 parts of2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-amine and 120 parts offormic acid is stirred and refluxed for 3 hours. The reaction mixture ispoured onto water and the whole is alkalized with ammonium hydroxide.The precipitated product is filtered off and crystallized fromN,N-dimethylformamide, yielding, after drying, 6.3 parts ofN-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)formamide; mp.256.8° C.

Example XXXIII

To a stirred mixture of 5.5 parts ofN-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)formamide and 80parts of hexamethylphosphoric triamide are added portionwise 1.24 partsof sodium hydride dispersion 75.8%. After stirring for 2 hours at roomtemperature, there are added dropwise 4.9 parts of dimethyl sulfate.Upon completion, stirring is continued for 3 hours at 50° C. andovernight at room temperature. 4-Methyl-2-pentanone and water are addedand the layers are separated. The aqueous phase is extracted twice with4-methyl-2-pentanone. The combined organic phases are washed with water,dried, filtered and evaporated. The residue is crystallized frommethylbenzene. The product is filtered off and dried, yielding 1.5 partsofN-(2,3-dihydro-7-methylimidazo[2,1-b]benzothiazol-6-yl)-N-methylformamide;mp. 164.2° C.

Example XXXIV

A stirred and warm solution of 4.5 parts ofN-ethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine in 30 parts ofacetic acid is acidified with 2-propanol, saturated with gaseoushydrogen chloride. After cooling to room temperature, the formedhydrochloride salt is filtered off and dried at 150° C., yielding 2.1parts of N-ethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-aminemonohydrochloride; mp. 289.2° C.

Example XXXV

A mixture of 3 parts of 2,3-dihydroimidazo[2,1-b]benzothiazol-7-amine,15 parts of 2-bromo-2-methylpropane and 13.5 parts ofN,N-dimethylformamide is stirred for 20 hours at 80° C. The reactionmixture is poured onto 50 parts of water. The precipitated product isfiltered off, washed successively with water, 2-propanol and2,2'-oxybispropane, and dried, yielding 3 parts ofN-(2,3-dihydroimidazo[2,1-b]benzothiazol-7-yl)formamidemonohydrobromide; mp. 287.3° C.

Example XXXVI

To a stirred mixture of 3 parts of imidazo[2,1-b]benzothiazol-6-amine,16 parts of acetic acid and 32 parts of water is added dropwise asolution of 1.54 parts of potassium cyanate in 32 parts of water(slightly exothermic reaction). Upon completion, stirring is continuedovernight at room temperature. The reaction mixture is alkalized withammonium hydroxide. Upon stirring, the product is precipitated. It isfiltered off and dried, yielding 3 parts ofN-(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)urea; mp. +300° C. ExampleXXXVII

To a stirred mixture of 4 parts of(2,3-dihydroimidazo[2,1-b]benzothiazol-6-yl)phenylmethanonemonohydrochloride, 3 parts of sodium methoxide and 60 parts of methanolare added portionwise 1.5 parts of sodium borohydride. Upon completion,stirring is continued for 5 minutes at reflux temperature. The reactionmixture is cooled and upon the addition of water, the product is allowedto crystallize. It is filtered off and recrystallized from4-methyl-2-pentanone. The product is filtered off and dried, yielding0.4 parts of 2,3-dihydro-α-phenylimidazo[2,1-b]benzothiazole-6-methanol;mp. 175.2° C.

Example XXXVIII

A mixture of 10 parts of 7-ethoxy-2,3-dihydroimidazo[2,1-b]benzothiazoleand 150 parts of hydrobromic acid solution 48% in glacial acetic acid isstirred and refluxed overnight. The reaction mixture is evaporated. Thesolid residue is washed with ethanol and crystallized from ethanol 80%.The product is filtered off and dried, yielding 8 parts of2,3-dihydroimidazo[2,1-b]benzothiazol-7-ol monohydrobromide; mp. 259.9°C.

Example XXXIX A mixture of 3.8 parts of2,3-dihydro-7-methylimidazo[2,1-b]benzothiazole, 11 parts of(2-bromoethyl)benzene and 40 parts of acetonitrile is stirred andrefluxed for 8 hours. After cooling, the precipitated product isfiltered off and dried, yielding 6 parts of2,3-dihydro-7-methyl-1-(2-phenylethyl)imidazo[2,1-b]benzothiazoliumbromide; mp. 150.6° C.

In a similar manner there are also prepared:

7-butyl-1-hexyl-2,3-dihydroimidazo[2,1-b]benzothiazolium bromide; mp.178.7° C.;

2,3-dihydro-7-methyl-1-(2-propynyl)imidazo[2,1-b]benzothiazoliumbromide; mp. 242.5° C.;

6-amino-7-butyl-1-(2,6-dichlorophenylmethyl)-2,3-dihydroimidazo[2,1-b]benzothiazoliumchloride monohydrate; mp. 152° C.;

2,3-dihydro-1-(1-methylethyl)-6-(propylamino)imidazo[2,1-b]benzothiazoliumbromide; mp. 237.7° C.;

1-(2,6-dichlorophenylmethyl)-6-(ethylamino)-2,3-dihydroimidazo[2,1-b]benzothiazoliummonochloride; mp. 268.3° C.; and

6-(ethylamino)-2,3-dihydro-1-methylimidazo[2,1-b]benzothiazoliummonoiodide; mp. 273.8° C.

Example XL

To a stirred mixture of 10 parts of diethyl2-[(2,3-dihydroimidazo[2,1-b]benzothiazol-7-ylamino)methylene]propanedioate,1.1 parts of sodium hydride dispersion 76.8% and 100 parts ofhexamethylphosphoric triamide are added 13.2 parts of 1-bromohexane. Thewhole is stirred over weekend at 50° C. The reaction mixture is pouredonto methylbenzene. The latter is washed three times with water, dried,filtered and evaporated. The residue solidifies on triturating in1,1'-oxybisethane. The product is filtered off and crystallized from4-methyl-2-pentanone, yielding 4.5 parts of7-{[2,2-bis(ethoxycarbonyl)ethenyl]hexylamino}-1-hexyl-2,3-dihydroimidazo[2,1-b]benzothiazoliumbromide; mp. 162° C.

Example XLI

To a stirred solution of 0.5 parts of2,3-dihydro-N-(1-methylethyl)imidazo[2,1-b]benzothiazol-8-amine in 16parts of methanol is added a solution of 0.184 parts of copperdichloride dihydrate in 4 parts of methanol. The precipitated product isfiltered off, boiled in 40 parts of methanol, filtered off again anddried in vacuo at room temperature. The product is further dried for 2hours in vacuo at 120° C., yielding 0.47 parts ofbis[2,3-dihydro-N-(1-methylethyl)imidazo[2,1-b]benzothiazol-8-amine]copper (2+) dichloride; mp. 207.9° C.

What is claimed is:
 1. A chemical compound selected from the groupconsisting of a 2,3-dihydroimidazo[2,1-b]benzothiazole which maystructurally by represented by the formula ##STR41## and thepharmaceutically acceptable acid addition salts thereof, thepharmaceutically acceptable imidazo[2,1-b]benzothiazolium salts offormula ##STR42## and metal salt complexes thereof with a transitionmetal salt wherein: R¹ and R³ are each independently selected from thegroup consisting of hydrogen and lower alkyl;R² and R⁴ are eachindependently selected from the group consisting of hydrogen, loweralkyl, aryl, aryllower alkyl, lower alkyloxylower alkyl or aryloxyloweralkyl; R⁵, R⁶, R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen; nitro; alkyl having from 1 to 20 carbon atoms;cycloalkyl having from 3 to 6 carbon atoms; hydroxy; lower alkyloxy;aryloxy; α-hydroxyarylmethyl; amino; mono- and dialkyl-amino; mono-, di-and trihalo-lower alkyl-amino; lower alkenylamino; lower alkynylamino(aryllower alkyl)amino; (lower alkyloxy-lower alkyl)amino;(hydroxy-lower alkyl)amino; (aryloxy-lower alkyl)amino; [mono- anddi(lower alkyl)amino-lower alkyl]amino; lower alkanoylamino; N-(loweralkyl)-lower alkanoylamino; aminocarbonylamino; (1-loweralkyl-4-piperidinyl)amino; cycloalkylamino wherein said cycloalkylrepresents a mono-, bi-, tri- or tetracyclic hydrocarbon radical havingfrom 3 to 10 carbon atoms; and a radical of the formula ##STR43##wherein R¹⁰ is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl and lower alkynyl; or when taken together R⁵ andR⁶, R⁶ and R⁷, or R⁷ and R⁸ may form a tri- or tetramethylene bridge orcomplete a fused benzene nucleus; R⁹ is a member selected from the groupconsisting of lower alkyl, lower alkenyl, lower alkynyl and aryl loweralkyl; and X is a pharmaceutically acceptable anion and n represents thevalency of the anion;wherein aryl as used in the foregoing definitionsis phenyl, optionally substituted with 1 to 3 substituents eachindependently selected from the group consisting of halo, lower alkyl,lower alkyloxy and trifluoromethyl; and aroyl is arylcarbonyl.
 2. Achemical compound selected from the group consisting ofN-ethyl-2,3-dihydroimidazo[2,1-b]benzothiazol-6-amine, thepharmaceutically acceptable acid addition salts thereof, thepharmaceutically acceptable corresponding imidazo[2,1-b]benzothiazoliumsalts thereof and the metal salt complexes thereof with a transitionmetal salt.